Postnatal Methylmercury Delivery Using a Polymer and Halloysite Formulation The developing nervous system is especially sensitive to exposure to methylmercury (MeHg), a significant environmental contaminant. Experimental models are required to characterize human exposure, but modeling the full human gestational period in a rodent requires ex- posure both during gestation and during the rodent's early postnatal period. This is because regions that are sensitive to MeHg, including the prefrontal cortex and cerebellum, show significant development during the last trimester of human gestation, and show similar development during the first 7-10 days of rodent life. Unfortunately, the bioavailability of MeHg in milk is very low so it is not possible to produce significant postnatal exposure by exposing the lactating dam. A convenient technique for producing postnatal exposure simply, reliably, inexpensively, and a sustained, low-dose manner would facilitate the study of critical periods of exposure. In the proposed studies, an injectable polymer-based formulation will be developed that can be used to provide chronic, low-dose exposure to MeHg in the post-natal rodent. If successful, the approach could be used for any age group and possibly for other metals. MeHg will be bound to halloysite and this MeHg/halloysite complex will then be dispersed in a polymer matrix. Two different approaches will be examined, one based on a thermoresponsive gel and a second on a thermoplastic material. Both will be in a liquid form at cool temperatures so they can be injected easily with a syringe but, upon exposure to the mouse's warmer body temperature, will become more viscous and therefore will release MeHg slowly. The studies will be conducted in four phases. First, benchtop studies will be conducted to identify candidate formulations for administration to a mouse pup. Second, dose-ranging studies will be conducted to determine the relation between MeHg loading on to the halloysite and brain MeHg after five days. Third, postnatal kinetic studies will be conducted to determine the rate of uptake and elimination of MeHg after injection on postnatal day 1. Finally, the kinetics of pre + postnatal exposure will be examined to determine the smoothness of the transition from fetal exposure via maternal drinking water to postnatal exposure via the formulation. A successful formulation will greatly facilitate the study of MeHg exposure during the crucial postnatal period. Current techniques, such as daily dosing, are highly labor intensive and more primitive approaches, such as injection of MeHg in saline, produce an unrealistic MeHg pulse that decreases with time.
Methylmercury is toxic to the developing nervous system. To model human methylmercury exposure in the laboratory using rodent models, it is necessary to produce exposure during the rodent equivalent of the human third trimester of pregnancy, which is when the brain growth spurt occurs. This period of brain development occurs during the first 7-10 days of rodent life. Since methylmercury does not appear in milk, it is difficult to expose th nursing mouse pup. We propose to develop a polymer-based formulation in which methylmercury is dispersed. This formulation is liquid at cool temperatures but once injected will assume a firmer, more viscous state so it will provide sustained, low-level exposure to the neonatal mouse. This will permit scientists to investigate the critical period of brain development that occurs in the human third trimester and the neonatal rodent.
